Estimating Sensitivity and Specificity from a Phase 2 Biomarker Study that Allows for Early Termination

Development of a disease screening biomarker involves several phases. In phase 2 its sensitivity and specificity is compared with established thresholds for minimally acceptable performance. Since we anticipate that most candidate markers will not prove to be useful and availability of specimens and funding is limited, early termination of a study is appropriate if accumulating data indicate that the marker is inadequate. Yet, for markers that complete phase 2, we seek estimates of sensitivity and specificity to proceed with the design of subsequent phase 3 studies. We suggest early stopping criteria and estimation procedures that adjust for bias caused by the early termination option. A novel aspect of our approach is to focus on properties of estimates conditional on reaching full study enrollment. We propose the conditional-UMVUE and contrast it with other estimates, including naive estimators, the well studied unconditional-UMVUE and the mean and median Whitehead adjusted estimators. The conditional-UMVUE appears to be a very good choice